Project 1 Summary Fibrotic lung disease such as IPF have no effective therapies in part because of very poor access into lung tissue. The micovascular endothelium represents a key barrier to effective delivery. Targeting intravenous therapies to reach inside the tissue where they can be most effective is a longstanding, formidable clinical challenge. We have developed a caveolae-targeting strategy which rapidly concentrates intravenously injected antibodies and their attached cargo inside lung tissue. The overall objective of Project 1 is to define how well this highly innovative strategy can deliver anti-fibrotic agents specifically into lung, ultimately to create more effective treatments for major lung diseases. The Specfic Aims of this Project are: Aim 1: To investigate EC and lung processing of immunocomplexes targeting rat lungs in vivo; Aim 2: to investigate EC and lung processing of nanoparticles (NP) targeting rat lungs in vivo. Aim 3: to evaluate APP2 expression in human organs and to evaluate targeting of antibodies, immunocomplexes and NPs to human lungs. We have established that caveolae in rodents can rapidly pump antibodies to APP2 (mAPP2) across the EC barrier to reach parenchymal cells deep within lung tissue. We will now evaluate the ability of the caveolae and mAPP2 to deliver anti-fibrotic compounds into lung. Conjugation of mAPP2 to select anti-fibrotic biological agents (TGF- antibody & Thy-1) and NPs loaded with small chemo-therapeutics will occur in Core B. Lung delivery, penetration and tissue accumulation of these retargeted therapies will be studied in rodent and humans using multiple imaging modalities (Core C) including SPECT-CT, intravital microscopy, immunohisto-chemistry and electron microscopy. Successful targeted therapies developed and validated in this project can have a signficant clinical impact by increasing efficacy at lower doses and reducing adverse side effects. Our new imaging approaches accelerate clinical translation by bridging the gap between preclinical and clinical studies. This work represents a prototype for caveolae-targeted therapies and could initiate a paradigm shift in the way therapies are delivered for many diseases. This shift shift in drug delivery offers new hope for patients with devastating lung diseases such as IPF.